Variations inPROKR2, But NotPROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia

Abstract

Context:Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).Objective:We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.Results:We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C—the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2−/− mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exception of reduced LH; this was inconsistent with patient phenotypes and more analogous to the healthy mother, although she did not have KS, unlike the Prokr2−/− mice.Conclusions:The role of PROKR2 in the etiology of CH, SOD, and KS is uncertain, as demonstrated by no clear phenotype-genotype correlation; loss-of-function variants in heterozygosity or homozygosity can be associated with these disorders. However, we report a phenotypically normal parent, homozygous for p.L173R. Our data suggest that the variants identified herein are unlikely to be implicated in isolation in these disorders; other genetic or environmental modifiers may also impact on the etiology. Given the phenotypic variability, genetic counseling may presently be inappropriate.

Spectrum of Clinical and Associated MR Imaging Findings in Children with Olfactory Anomalies

“…Most interesting, a genetic link may be present between Kallmann syndrome and optic hypoplasia syndrome with loss-offunction mutations in PROKR2 found in both. 19 The association of anterior pituitary dysfunction may relate to the proximity of the developing adenohypophyseal and olfactory placodes. 2 Brain MR imaging protocols may benefit from the routine addition of coronal T2-weighted imaging, which would be optimal for evaluation of the olfactory apparatus and optic nerves.…”

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

“…Interestingly, the majority of these variants had already been reported in patients with isolated hypogonadotroph hypogonadism. Surprisingly, murine models with homozygous inactivation of Prokr2 showed predominantly normal hypothalamo-pituitary development and terminal cell differentiation, except for LH secreting cells (22). The role of PROKR2 in pituitary development, though highly plausible, remains to date speculative.…”

Análise molecular dos genes NEUROD4, FGFR1 e PROKR2 em pacientes com hipopituitarismo congênito

“…O receptor, do tipo tirosina-quinase, consiste de 3 alças extracelulares Ig-like, um domínio transmembrana, um domínio acidic box e 2 domínios intracelulares tirosina-quinase (24)(25)(26) .…”

“…As duas primeiras foram consideradas deletérias nos estudos funcionais, evidenciando, de acordo com os autores, um papel causativo no fenótipo (38) . (39) . Neste estudo, a variante p.Leu173Arg, deletéria no estudo funcional, foi herdada pelo paciente de sua mãe não afetada que apresentava a variante em homozigose.…”

“…Neste estudo, a variante p.Leu173Arg, deletéria no estudo funcional, foi herdada pelo paciente de sua mãe não afetada que apresentava a variante em homozigose. De modo que esta correlação genótipo-fenótipo pobre levou os autores a concluir que a contribuição das variantes da PROKR2 para o fenótipo de hipopituitarismo é duvidosa (39) .…”